Glaucoma, manifesting itself by the turbidity and opacity of ocular cornea, endangers especially persons of age over 50 and can eventually lead to total blindness. Observations indicate that there is a relation between glaucoma and the intraocular pressure (IOP), and that a pathologically increased IOP, also known as ocular hypertension, is the principal condition for developing glaucoma. In the past, attempts have been made to eliminate, or at least to retard, the progress of the disease by lowering IOP either by surgery or by drug medication.
It is known that in patients treated for various reasons by adrenergic drugs, i.e. drugs exerting a physiological activity toward adrenoreceptors, a lowering of IOP is frequently encountered as a side effect. This decrease in IOP was observed not only with orally administered adrenoreceptor antagonists (especially those blocking .beta.-receptors such as propranolol and practolol), but also, for not fully understood reasons, with adrenoreceptor agonists, especially .beta.-adrenergic stimulators such as terbutaline [2-tert-butyl-1-(3,5-dihydroxyphenyl)-ethanol, disclosed in U.S. Pat. No. 4,011,258] which is a potent vaso- and bronchodilator, cf. K. Wettrell et al.: Experimental Eye Research (1977) 24, 613-619 and the references cited therein.
In order to utilize this general effect in ophthalmologic therapeutic practice, especially in control of excessive IOP (i.e. the ocular hypertension) and glaucoma, the primary overall adrenergic effect of an orally administered drug had to be minimized, whereas the desirable "side-effect" onto the eye, i.e. the lowering of IOP, should be retained if not potentiated. Fortunately, animal experiments early indicated that these drugs exert their beneficial effect also by topical administration. On this basis, epinephrine has been widely used anti-glaucoma agent. However, a pervasive side effect of epinephrine therapy is mydriasis, which is unfortunately largely undissociable from the drug's ocular hypotensive action. More recently, epinephrine dipivalic ester, dipivefrin, has undergone extensive development specifically intended for use in ocular hypertension and glaucoma. The substance is about 10 times more potent (i.e. it brings a comparable effect in a 10 times smaller dose) than the parent compound, but is not more efficient than epinephrine in lowering IOP (i.e. the maximum available decrease in IOP irrespectively of doses is the same in both substances). The smaller dose of the ester necessary to lower IOP obviates some of the undesirable extraocular side effects encountered with the relatively high therapeutic doses necessary with epinephrine. The mydriasis, however, as well as other intraocular side effects accompanying epinephrine, are unfortunately likewise present with use of the dipivalate.
A more promising approach was expected by the topical application of the .beta.-adrenoreceptor stimulators, whose ocular hypertensive effect by oral route has been discussed above. In spite of some controversial results [e.g. a potent .beta.-adrenergic stimulator prenalterol was found ineffective in lowering IOP in normotensive human eye by oral administration, c.f. A. Alm et al.: Acta Ophthalmologica 59, 882-887 (1981)], it has been generally established that by either oral or topical administration, the decreases in IOP were significantly more pronounced with drugs having strong .beta..sub.2 -adrenoreceptor stimulating activity, such as isoproterenol, metaproterenol, salbutamol and terbutaline, cf. D. E. Potter and J. M. Rowland: Experimental Eye Research (1978) 27, 615-625. This association of lowering IOP with the adrenergic activity, and especially with the .beta..sub.2 -receptor-stimulating, vascular activity has been demonstrated also by suppressing experimental ocular hypertension in rabbits, cf. J. M. Rowland and D. E. Potter: Experimental Eye Research (1980) 30, 93-104. An analogous correlation was also found for both normotensive and hypertensive human eye.
In addition to terbutaline, said U.S. Pat. No. 4,011,258 also disclosed corresponding 3',5'-diesters of the parent compound with C.sub.2 -C.sub.5 fatty acids, especially the 3',5'-diisobutyrate, ibuterol, for use as bronchodilators. However, the esters as such have only negligible .beta..sub.2 -stimulating activity and develop their effect only after having been hydrolyzed in situ by endogenous esterases to form the .beta..sub.2 -adrenoreceptor-stimulating parent substance terbutaline, see O. A. T. Olsson et al. Acta Pharmacologica et Toxicologica 35, 76 (1974). Hence, the esters, including ibuterol, are bronchodilators of an approximately equal potency as the parent drug, and ibuterol failed to offer the expected advantage over terbutaline when applied as bronchodilator by inhalation in asthmatic patients, see N. Mcl. Johnson and S. W. Clarke: British Medical Journal 1977, 1006.
In the present invention, the unexpected finding has been made now that ibuterol [1-(3,5-diisobutyryloxyphenyl)-2-tertbutylamino)-ethanol], as compared to the parent terbutaline as standard, reveals surprisingly high effects in lowering IOP by topical application onto a mammal's eye. The experimental data, summarized in Table I, clearly establish that ibuterol not only possesses an increased potency but also an improved efficacy as compared to terbutaline. Whereas this reaches its greatest efficacy in decreasing IOP by approximately 7% at a dose of 100 .mu.l of a 2% solution, IOP reductions amounting more than 10% can be achieved with the same amount (100 .mu.l) of a much more diluted (0.05-0.1%) solution of ibuterol
TABLE 1 ______________________________________ Mean Decrease in IOP 1 Hour After Topical Instil.* dl-Terbutaline lbuterol Sulfate ** ***IOP-reduction ** ***IOP-reduction conc. % mm Hg .+-. SE conc. % mm Hg .+-. SE ______________________________________ 4 6.9 .+-. 0.8 0.1 9.8 .+-. 0.8 2 7.1 .+-. 0.8 0.05 10.4 .+-. 0.6 0.2 3.8 .+-. 0.7 0.01 6.2 .+-. 0.9 0.06 3.3 .+-. 0.9 0.005 7.7 .+-. 1.0 0.02 4.7 .+-. 1.4 0.001 4.2 .+-. 1.3 ______________________________________ *6 rabbits in each experimental group; **solution in distilled water, concentration calculated as w/vpercentage of free base; ***applied doses 100 .mu.l; SE = standard error